Epidemiological features of tuberculosis infection in a rural prefecture of Japan from 2007 to 2018

This study aimed to investigate the epidemiological features of reported tuberculosis (TB) infections in a western prefecture (Nagasaki Prefecture) from 2007 to 2018, and to identify the high-risk group for TB infection. The characteristics of 12 years of reported TB infections from the Nagasaki Prefectural Informational Center of Infectious Diseases were summarized by median (interquartile range [IQR]) and proportion; the annual TB infections’ notification rate regarding sex/age was calculated accordingly. The diagnosis of TB infection was made according to clinic symptoms and laboratory examination. In total, 4364 TB infections were reported in 2007 and 2018, with a median age (IQR) of 74 (55–84) years. The majority of TB infections were male (52.6%, 2297/4364), > 65 years (65.8%, 2869/4364), and indigenous (98.1%, 4276/4364). Among active TB, 66.9% (1833/2740) had pulmonary TB, and 25.3% (694/2740) were diagnosed as extrapulmonary TB. The highest notification rate of TB infection was observed in the elderly male population (> 85 years). The annual notification rate of TB infections ranged between 19.4/and 34.0/100,000 for 12 years. The notification rates of TB infections were high in older people of both sexes, especially in men aged > 85. Therefore, appropriate interventions and health management are essential for TB control in (and with a focus on) the elderly population.

compares the characteristics of reported TB infections by sex, of which 2297 (52.6%) were male. The median age (IQR) of the reported TB infections was 74 (55-84), 65.8% of whom were ≥ 65 years old. Of the reported TB infections, 27.7% (1208) were between 75 and 84 years old, 31.5% (1373) were from Nagasaki City, which has the largest population in the prefecture, and 62.7% (2738) were active TB. According to clinical symptoms, consultation, and epidemiological considerations, droplets/droplet nuclei were identified as the possible transmission routes (3145 infections, 72.1%), and most cases were indigenous (4270 infections, 97.8%). 68.4% of the reported TB infections were unemployed, of which 2620/2983 were people older than 65; among those with a confirmed occupation (1230, 28.2%), 491 (39.9%) reported cases were from the medical and welfare sector. Table 2 further describes the 2740 active TB cases (2738 active TB and two active PTB confirmed dead cases). Of these active TB, 56.0% (1534) were male, the median age (IQR) was 74 (55-84), and 76.6% (2099) were senior citizens (≥ 65 years). Of the 2740 active TB, 66.9% (1833) had pulmonary tuberculosis, 25.3% (694) were diagnosed as extrapulmonary tuberculosis, and 7.8% (213) had both. Of the 1833 PTB cases, 62.7% (1149) were smear-positive PTB. Five Drug-Resistant TB (DR TB) cases were notified for the study period; the characteristics of DR TB and its close contact cases are in Supplementary material 1; no Multidrug-Resistant TB or Extensively Drug-resistant TB was reported from 2007 to 2018 in Nagasaki Prefecture.
The reported female TB infections were slightly younger than the males (p < 0.05). 70% of the male TB infections were older than 65, while only 61% of females were older than 65 (p < 0.0001). On the contrary, the females with active TB were slightly older than the males (p < 0.05). 58.7% of the males with active TB were older than 75, while 62.1% of females were older than 75 (p < 0.0001). The majority of reported female TB infections worked in the medical and welfare sector (79.7%), accommodation or restaurant business, and service industry, while the male TB infections primarily worked in medical and welfare sector, wholesale/retail business, agriculture and forestry, and construction industry. The proportion of notified asymptomatic pathogen holders (Type 2 of TB Notification) was significantly higher in females (41.0%) than in males (32.1%). No statistically significance was found regarding the type of active TB between the sexes. Table 3 portrays the clinical symptoms of the 4364 reported TB infections. The chief pulmonary symptoms include cough, phlegm, fever, chest pain, dyspnea, anorexia, and weight loss. Other symptoms such as night sweats, hemoptysis, erythema nodosum/induratum, and chest X-ray abnormalities (upper lobe infiltrates, cavitation, etc.) strongly suggest a PTB infection 23 . In addition, symptoms of the eight most affected extrapulmonary sites 24 were stratified by sex and age group. Infections at multiple extrapulmonary sites were observed in both sexes and across all ages, except for 0-14 years; only symptoms of the lymphatic system were noted. Approximately one-quarter of the reported TB infections did not present any TB-related symptoms. Figure 2a shows the annual accumulated TB infections, the proportion of the three notification types of TB infection (dead not included), the crude notification rate per 100,000 people of TB infections, active TB, and APH from 2007 to 2018.
During the study period, the reported TB infections declined from 2007 (364 in total, with 179 males and 185 females) to 2018 (296 in total, with 156 males and 140 females).   The 2740 active TB cases described in Table 2 are the sum of 2738 Active TB and 2 Dead (one confirmed of PTB and another of PTB + EPTB) previously mentioned in Table 1; PTB*: pulmonary tuberculosis; SPPTB*: smear-positive PTB; SNPTB*: smear-negative PTB; EPTB*: extrapulmonary tuberculosis; The Chi-square (χ 2 ) test/Mann-Whitney U test was used to assess differences in active TB according to sex with a p-value less than 0.05 is statistically significant.    Fig. 2c. Pleural TB remained the most common form of EPTB, followed by lymph node TB. Most EPTB were older than 65 years (693/865, 80.1%). Figure 3 shows the sex-and age-stratified notification rate of TB infections per 100,000 people in Nagasaki Prefecture from 2007 to 2018. A much higher notification rate was observed among older people, both men and women, but especially in the elderly male population. Men and women aged > 65 years accounted for 36.8% (1607/4364) and 28.9% (1262/4364) of all TB infections, respectively ( Table 1). The highest notification rate was noted in infections aged > 85 years in both sexes, followed by those between 75 and 84 years, and then between 65 and 74 years. A considerable increase in the notification rate was witnessed in men aged > 85 years between 2007 and 2010. The TB infections' notification rate was relatively stable and low in the youth population and among those ranging in age from 25 to 65 in both sexes. In the age groups of 65-74 years, 75-84 years, and older than 85, the TB infections' notification rate per 100,000 people in males was two, 2.2, and 2.5 times higher than in females, respectively. Table 4 summarizes the relevant time intervals of notified TB infections in Nagasaki Prefecture from 2007 to 2018. The median time from onset of symptoms to TB diagnosis for active TB cases was 30 days (IQR: 10-65), and 30 days (IQR: 12-63) for APH cases. Data on the presumed infection date for active TB is available for 503 active TB cases, and the median time from presumed infection date to onset of symptoms was 0 days (IQR: 0-64). The median time from first medical visit to TB diagnosis for active TB cases was four days (IQR: 0-17), and 0 days (IQR: 0-12) for APH cases. Most active TB and APH cases were identified and confirmed within six months.

Discussion
In this study, we investigated the epidemiological features of reported TB infections in Nagasaki Prefecture from 2007 to 2018. In Japan, the TB notification rate has been falling steadily since 1980 14,15 , and reached a historic low of 13.3 per 100,000 people for all forms of TB in 2017 13 . However, considerable variation exists among Japan's eight administrative regions. In Nagasaki Prefecture, located in the Kyushu region, the TB burden has remained relatively high over the past decade.
Between 2007 and 2018, there were 4364 reported TB infections in Nagasaki Prefecture, the notification rate of TB infections ranged between 19.4 and 34.0 cases, and the notification rate of active TB varied from 13.5 to 26.9 cases per 100,000 people. A high notification rate of TB infections occurred within the elderly population, especially in men older than 85 years. In the youth population (0-14 years), the TB infections' notification rate remained below 5 cases per 100,000 people, owing to the nearly 100% coverage rate of the BCG (Bacillus  www.nature.com/scientificreports/ Calmette-Guerin) vaccination from the tuberculosis control program 25 . However, on the other hand, in Nagasaki Prefecture, the high TB infection burden in the elderly population persisted (65.8% of TB infections were aged above 65). Like other parts of Japan, Nagasaki Prefecture is experiencing a severe population decline and aging transition 26 . Several studies have shown that TB in the elderly population has already become a crucial global health problem 4,[27][28][29] . The susceptibility to respiratory infections, including TB, increases with age, as aging has irreversible effects on both the innate and adaptive immune systems 30,31 . In terms of TB infection pathogenesis, aging affects the processes of the integumental barriers, microbial clearance mechanisms, and cellular immune responses 28,32 . TB in older people is often atypical 33 , or they exhibit non-specific symptoms and signs similar to those of other underlying ailments. Elderly patients may experience more adverse drug reactions, and some prevalent comorbidities in the aging population (e.g., diabetes mellitus) could increase the risk of developing active TB 28 . Although TB in the elderly is mostly due to the reactivation of a former infection 29 , a molecular epidemiological study from Yamagata Prefecture 34 indicated an association between increased TB infections and the recent transmission of M. tuberculosis in elderly people. Further investigation of the TB transmission pattern in Nagasaki Prefecture is required. The proportion of active EPTB patients (25%, 865/2339) in this study was similar to findings from other developed countries and regions: 15% in the U.S. 35 , 22.3% in Hong Kong (China) 36 , and 21.6% in Germany 37 .
Japan first engaged in international efforts to control TB by announcing the "Stop TB Japan Action Plan" in 2008 and initiating the "Stop TB Japan" in 2015, to reduce TB deaths by 10% worldwide 38 . Until 2012, the TB incidence rate was 16.7 per 100,000 people in Japan, which was four to five times higher than that of Western European countries. Japan is still categorized as a medium-burden TB country. Our study also showed that until 2014, the newly notified active TB cases and APH increased slightly in Nagasaki Prefecture. In addition to the high notification rate of TB infections within the elderly population, another notable finding is that the proportion of females working in the medical and welfare sector is very high among notified TB cases within working age. The primary concern regarding TB control is that citizens are losing interest in TB, and the provision of medical services might be degraded due to a lack of TB-related experience among health workers. Also, the gradual replacement of tuberculin skin tests with interferon-γ release assays for LTBI screening makes a higher efficacy diagnosis of TB infection, despite the high rate of BCG vaccination in Japan. After the WHO launched the "End TB Strategy" in 2014 3 , MHLW adopted the WHO's new strategy by re-addressing priorities and adjusting measures. Extensive screening and treatment of latent TB infection, especially for high-risk groups (the elderly, immigrants, etc.), the restructuring of the medical provision system, and reinforcement of TB control in megacities were considered in this revised strategy. The JATA/Research Institute of Tuberculosis (RIT), the Anti-Tuberculosis Women's Society, and other related organizations are joining forces to achieve the goal of making Japan a low-burden TB country (with an incidence rate of less than 10 per 100,000 people), as well as a 95% decrease in TB deaths by 2035.
Various factors have contributed to the current TB prevalence in Japan, such as homelessness and MDR-TB issues in the city of Osaka 39 as well as the presence of immigrants from high TB prevalence countries in Tokyo 40 . Our study shows that in Nagasaki Prefecture, elderly people are a high-risk group for TB infection. Thus, appropriate interventions and management are crucial for TB control in this vulnerable group. Active case findings among senior citizens, the identification of TB transmission settings, strengthening adherence to active TB and LTBI treatment in the older population, training staff in nursing homes, and other feasible interventions are essential to attaining the "End TB Strategy" goal by 2035.
This study has some limitations. First, it is a retrospective study using standard surveillance data from medical institutions and health centers; information on income, living conditions, lifestyle, medical history, and treatment records were not available. Second, the inference regarding the transmission method and the infected location was based only on the conclusions of training physicians. Third, this study does not have data on risk factors for tuberculosis infection, like tobacco use, alcoholism, drug abuse and crowding. Fourth, only a small portion of TB infections in our data was registered with a presumed infection date. Therefore, more completed data are needed to demonstrate the duration of latent infection's progress to active disease. Finally, the cause of TB infection (the reactivation of latent TB) was unclear.

Conclusions
This study investigated the epidemiological features of notified TB infections in Nagasaki Prefecture from 2007 to 2018. The overall notification rates of TB infections slightly increased between 2007 and 2014, then decreased in the ensuing years. TB infections mainly were reported in densely populated areas, people aged between 65 to 75 years, and from the medical and welfare sector among notified cases within working age. The notification rates of TB infections were high in older people of both sexes, especially in men aged > 85. Appropriate interventions and health management are urgently needed for TB control in the elderly population.

Data availability
The data used in this study were extracted from information center for infectious diseases of the Nagasaki Prefectural Institute of Environment and Public Health, which is publicly available at (https:// www. pref. nagas aki. jp/ bunrui/ hukus hi-hoken/ kanse nsho/ kansen-c/). The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.